title: [Ca²⁺] i-induced augmentation of the inward rectifier potassium current (IK1) in canine and human ventricular myocardium.
abstract: The inward rectifier K⁺ current (IK1) plays an important role in terminal repolarization and stabilization of the resting potential in cardiac cells. Although IK1 was shown to be sensitive to changes in intracellular Ca²⁺ concentration ([Ca²⁺]i), the nature of this Ca²⁺ sensitivity-in spite of its deep influence on action potential morphology-is controversial. Therefore, we aimed to investigate the effects of a nonadrenergic rise in [Ca²⁺]i on the amplitude of IK1 in canine and human ventricular myocardium and its consequences on cardiac repolarization. IK1, defined as the current inhibited by 10 μM Ba²⁺, was significantly increased in isolated canine myocytes following a steady rise in [Ca²⁺]i. Enhanced IK1 was also observed when [Ca²⁺]i was not buffered by ethylene glycol tetraacetic acid, and [Ca²⁺]I transients were generated. This [Ca²⁺]i-dependent augmentation of IK1 was largely attenuated after inhibition of CaMKII by 1 μM KN-93. Elevation of [Ca²⁺]o in multicellular canine and human ventricular preparations resulted in shortening of action potentials and acceleration of terminal repolarization. High [Ca²⁺]o enhanced the action potential lengthening effect of the Ba(2+)-induced IK1 blockade and attenuated the prolongation of action potentials following a 0.3-μM dofetilide-induced IKr blockade. Blockade of IKs by 0.5 μM HMR-1556 had no significant effect on APD90 in either 2 mM or 4 mM [Ca²⁺]o. It is concluded that high [Ca²⁺]i leads to augmentation of the Ba²⁺-sensitive current in dogs and humans, regardless of the mechanism of the increase. This effect seems to be at least partially mediated by a CaMKII-dependent pathway and may provide an effective endogenous defense against cardiac arrhythmias induced by Ca²⁺ overload.
authors.affiliation: Division of Cardiovascular Pharmacology, Hungarian Academy of Sciences, University of Szeged, Szeged, Hungary.
authors.forename: Norbert
authors.initials: N
authors.lastname: Nagy
authors.forename: Károly
authors.initials: K
authors.lastname: Acsai
authors.forename: Anita
authors.initials: A
authors.lastname: Kormos
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Sebők
authors.forename: Attila S
authors.initials: AS
authors.lastname: Farkas
authors.forename: Norbert
authors.initials: N
authors.lastname: Jost
authors.forename: Péter P
authors.initials: PP
authors.lastname: Nánási
authors.forename: Julius Gy
authors.initials: JG
authors.lastname: Papp
authors.forename: András
authors.initials: A
authors.lastname: Varró
authors.forename: András
authors.initials: A
authors.lastname: Tóth
mesh_terms: D000200:Action Potentials; D000818:Animals; D001464:Barium / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors; D004285:Dogs; D006352:Heart Ventricles / Q000166:cytology*; D006801:Humans; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D010627:Phenethylamines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D016276:Ventricular Function
chemical_list: D010627:Phenethylamines; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D013449:Sulfonamides; D001464:Barium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C063533:dofetilide; D011188:Potassium; D002118:Calcium